Meeting News

ESCAPE-NA1: Nerinetide benefit unclear in endovascular therapy for ischemic stroke

Mayank Goyal
Michael D. Hill

Among patients with major acute ischemic stroke who underwent endovascular therapy, those assigned IV nerinetide did not have improved outcomes compared with those assigned placebo, according to results from the ESCAPE-NA1 trial presented at the International Stroke Conference.

However, nerinetide conferred better rates of functional independence and survival than placebo in patients who were not treated with alteplase (Activase, Genentech).

The researchers enrolled 1,105 patients with acute ischemic stroke who had endovascular therapy and, if supported by guidelines, IV alteplase. Patients were randomly assigned to 2.6 mg/kg of IV nerinetide (NA-1, NoNO Inc.), a postsynaptic density protein 95 (PSD-95) inhibitor (mean age, 71 years; 49% women), or placebo (mean age, 70 years; 51% women).

Nerinetide targets PSD-95 and inhibits signaling that leads to neuronal toxicity and thus may be neuroprotective, potentially providing benefit beyond reperfusion, Mayank Goyal, MD, professor of neuroradiology at Hotchkiss Brain Institute and the department of radiology, University of Calgary, Alberta, Canada, and director of imaging and endovascular treatment for the Calgary Stroke Program, said during a presentation.

“Nerinetide is a promising agent that has shown neuroprotection in cell cultures, rodents, primates and in a phase 2 ENACT trial, which was in patients undergoing endovascular repair of intracranial aneurysms, which firstly showed the safety of NA-1 and secondly showed reduction in ischemic infarcts on diffusion-weighted MRI in patients treated with nerinetide,” Goyal said.

The findings were simultaneously published in The Lancet.

Functional independence

The primary endpoint of functional independence at 90 days, defined as a modified Rankin Scale score of 0 to 2, was achieved by 61.4% of patients assigned nerinetide and 59.2% of those assigned placebo (adjusted RR = 1.04; 95% CI, 0.96-1.14), Michael D. Hill, MD, MSc, FRCPC, professor of clinical neurosciences at Hotchkiss Brain Institute, and director of the stroke unit for the Calgary Stroke Program, said during the presentation.

Hill noted, however, that nerinetide bested placebo for the primary endpoint in patients who did not receive alteplase (nerinetide, 59.3%; placebo, 49.8%; aRR = 1.18; 95% CI, 1.01-1.38) but not in those who received alteplase (nerinetide, 62.7%; placebo, 65.7%; aRR = 0.97; 95% CI, 0.87-1.08; P for interaction = .033).

“In the group that did not receive standard of care IV tissue plasminogen activator, about 40% of the overall population, there is a substantial treatment effect,” Hill said. “In the group that did receive alteplase, it’s absolutely flat, and maybe even a slightly negative treatment effect for nerinetide.”

Mortality rates at 90 days were 12.2% in the nerinetide group and 14.4% in the placebo group (aRR = 0.84; 95% CI, 0.63-1.13), but there was a mortality benefit from nerinetide in those not treated with alteplase (nerinetide, 12.8%; placebo, 20.3%; aRR = 0.66; 95% CI, 0.44-0.99; adjusted HR = 0.56; 95% CI, 0.34-0.95), according to the researchers.

“It appears that in the alteplase group, there’s a substantial reduction in the available nerinetide. We had a small group of patients with pharmacokinetic data, and ... we think the alteplase was activating proteases, which were chewing up the drug.”

The NIH Stroke Scale score at 90 days was similar in both groups, with 58.3% of the nerinetide group and 57.6% of the placebo group having a score of 0 to 2 (aRR = 1.01; 95% CI, 0.92-1.11), the researchers found.

Serious adverse events were similar between the groups (aRR = 0.92; 95% CI, 0.79-1.09), according to the researchers.

Modified Barthel Index of 95 to 100 (nerinetide, 62.1%; placebo, 60.3%; aRR = 1.03; 95% CI, 0.94-1.12) and modified Rankin Scale score of 0 to 1 (nerinetide, 40.4%; placebo, 40.6%; aRR = 0.98; 95% CI, 0.85-1.12) did not differ, the researchers found.

“The compelling parts of the argument for nerinetide in the no-alteplase group is that there is a large statistical effect size at 9.5%, there’s a clear reduction in infarct volume, there’s a mortality benefit overall and the pharmacological data show that the reason we didn’t have any effect in the alteplase group was because, in that group, there was a substantial reduction in available drug,” Hill said. “We think we have provided perhaps the first clear evidence in humans that neuroprotection is possible. We know we are going to have to do more studies, and we are looking forward to doing them.”

No translation

In a related editorial published in The Lancet, Graeme J. Hankey, MBBS, MD, FRCP, FRCPEdin, FRACP, FAHA, FESO, FAAHMS, FWSO, professor of neurology at the University of Western Australia, wrote, “Once again, the favorable effects of a neuroprotective drug reported consistently in preclinical models of brain ischemia did not translate to clinical efficacy in humans with brain ischemia.”

Hankey wrote that although the alteplase-related data “might be a chance finding or confounded by the indication for alteplase, complementary pharmacokinetic data in a small number of patients treated with nerinetide showed that alteplase lowered plasma concentrations of nerinetide, probably by converting plasminogen to plasmin, which cleaves peptide bonds not only in fibrin but also in the eicosapeptide nerinetide.” – by Erik Swain

References:

Hill MD, et al. LB2. Presented at: International Stroke Conference; Feb. 19-21, 2020; Los Angeles.

Hankey G. Lancet. 2020;doi:10.1016/S0140-6736(20)30316-0.

Hill MD, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)30258-0.

Disclosures: The study was funded in part by NoNO Inc. Hill reports he received research grants from Alberta Innovates, Boehringer Ingelheim Canada, Medtronic, NoNO Inc. and Stryker. Please see the study for all other authors’ relevant financial disclosures. Hankey reports he received honoraria from the American Heart Association, AC Immune, Bayer, Bristol-Myers Squibb and Medscape.

Mayank Goyal
Michael D. Hill

Among patients with major acute ischemic stroke who underwent endovascular therapy, those assigned IV nerinetide did not have improved outcomes compared with those assigned placebo, according to results from the ESCAPE-NA1 trial presented at the International Stroke Conference.

However, nerinetide conferred better rates of functional independence and survival than placebo in patients who were not treated with alteplase (Activase, Genentech).

The researchers enrolled 1,105 patients with acute ischemic stroke who had endovascular therapy and, if supported by guidelines, IV alteplase. Patients were randomly assigned to 2.6 mg/kg of IV nerinetide (NA-1, NoNO Inc.), a postsynaptic density protein 95 (PSD-95) inhibitor (mean age, 71 years; 49% women), or placebo (mean age, 70 years; 51% women).

Nerinetide targets PSD-95 and inhibits signaling that leads to neuronal toxicity and thus may be neuroprotective, potentially providing benefit beyond reperfusion, Mayank Goyal, MD, professor of neuroradiology at Hotchkiss Brain Institute and the department of radiology, University of Calgary, Alberta, Canada, and director of imaging and endovascular treatment for the Calgary Stroke Program, said during a presentation.

“Nerinetide is a promising agent that has shown neuroprotection in cell cultures, rodents, primates and in a phase 2 ENACT trial, which was in patients undergoing endovascular repair of intracranial aneurysms, which firstly showed the safety of NA-1 and secondly showed reduction in ischemic infarcts on diffusion-weighted MRI in patients treated with nerinetide,” Goyal said.

The findings were simultaneously published in The Lancet.

Functional independence

The primary endpoint of functional independence at 90 days, defined as a modified Rankin Scale score of 0 to 2, was achieved by 61.4% of patients assigned nerinetide and 59.2% of those assigned placebo (adjusted RR = 1.04; 95% CI, 0.96-1.14), Michael D. Hill, MD, MSc, FRCPC, professor of clinical neurosciences at Hotchkiss Brain Institute, and director of the stroke unit for the Calgary Stroke Program, said during the presentation.

Hill noted, however, that nerinetide bested placebo for the primary endpoint in patients who did not receive alteplase (nerinetide, 59.3%; placebo, 49.8%; aRR = 1.18; 95% CI, 1.01-1.38) but not in those who received alteplase (nerinetide, 62.7%; placebo, 65.7%; aRR = 0.97; 95% CI, 0.87-1.08; P for interaction = .033).

“In the group that did not receive standard of care IV tissue plasminogen activator, about 40% of the overall population, there is a substantial treatment effect,” Hill said. “In the group that did receive alteplase, it’s absolutely flat, and maybe even a slightly negative treatment effect for nerinetide.”

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Mortality rates at 90 days were 12.2% in the nerinetide group and 14.4% in the placebo group (aRR = 0.84; 95% CI, 0.63-1.13), but there was a mortality benefit from nerinetide in those not treated with alteplase (nerinetide, 12.8%; placebo, 20.3%; aRR = 0.66; 95% CI, 0.44-0.99; adjusted HR = 0.56; 95% CI, 0.34-0.95), according to the researchers.

“It appears that in the alteplase group, there’s a substantial reduction in the available nerinetide. We had a small group of patients with pharmacokinetic data, and ... we think the alteplase was activating proteases, which were chewing up the drug.”

The NIH Stroke Scale score at 90 days was similar in both groups, with 58.3% of the nerinetide group and 57.6% of the placebo group having a score of 0 to 2 (aRR = 1.01; 95% CI, 0.92-1.11), the researchers found.

Serious adverse events were similar between the groups (aRR = 0.92; 95% CI, 0.79-1.09), according to the researchers.

Modified Barthel Index of 95 to 100 (nerinetide, 62.1%; placebo, 60.3%; aRR = 1.03; 95% CI, 0.94-1.12) and modified Rankin Scale score of 0 to 1 (nerinetide, 40.4%; placebo, 40.6%; aRR = 0.98; 95% CI, 0.85-1.12) did not differ, the researchers found.

“The compelling parts of the argument for nerinetide in the no-alteplase group is that there is a large statistical effect size at 9.5%, there’s a clear reduction in infarct volume, there’s a mortality benefit overall and the pharmacological data show that the reason we didn’t have any effect in the alteplase group was because, in that group, there was a substantial reduction in available drug,” Hill said. “We think we have provided perhaps the first clear evidence in humans that neuroprotection is possible. We know we are going to have to do more studies, and we are looking forward to doing them.”

No translation

In a related editorial published in The Lancet, Graeme J. Hankey, MBBS, MD, FRCP, FRCPEdin, FRACP, FAHA, FESO, FAAHMS, FWSO, professor of neurology at the University of Western Australia, wrote, “Once again, the favorable effects of a neuroprotective drug reported consistently in preclinical models of brain ischemia did not translate to clinical efficacy in humans with brain ischemia.”

Hankey wrote that although the alteplase-related data “might be a chance finding or confounded by the indication for alteplase, complementary pharmacokinetic data in a small number of patients treated with nerinetide showed that alteplase lowered plasma concentrations of nerinetide, probably by converting plasminogen to plasmin, which cleaves peptide bonds not only in fibrin but also in the eicosapeptide nerinetide.” – by Erik Swain

References:

Hill MD, et al. LB2. Presented at: International Stroke Conference; Feb. 19-21, 2020; Los Angeles.

Hankey G. Lancet. 2020;doi:10.1016/S0140-6736(20)30316-0.

Hill MD, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)30258-0.

Disclosures: The study was funded in part by NoNO Inc. Hill reports he received research grants from Alberta Innovates, Boehringer Ingelheim Canada, Medtronic, NoNO Inc. and Stryker. Please see the study for all other authors’ relevant financial disclosures. Hankey reports he received honoraria from the American Heart Association, AC Immune, Bayer, Bristol-Myers Squibb and Medscape.

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